PROJECT SUMMARY Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in the US. Although COPD occurs predominantly in smokers, it is unknown why only a minority of smokers (~20-40%) develop chronic airflow limitation or destruction of distal airspaces (emphysema). The difference susceptibility to tobacco smoke could be explained by differences in genetics or environment, which lead to activation or repression of pathways that are important in the pathogenesis and progression of COPD. Recent advances in high throughput omics (whole genome sequencing, DNA methylation, RNA-Seq, proteomics and metabolomics) applied to NHLBI cohorts now permits a comprehensive assessment of the molecular profiles of susceptible patients. This proposal will use sparse multiple canonical correlation network analysis (SmCCNet) to integrate these existing -omics data from three NHLBI cohorts: COPDGene, Jackson Heart Study, and SPIROMICS. The three independent cohorts will allow replication of specific molecular networks which can be used to target new therapies or more precise prognostic information to individuals (i.e., precision medicine). The first two of these cohorts have large numbers of African American subjects, who are underrepresented in omics studies. We will perform population specific analyses, which will allow us to determine which molecular signatures and pathways might be specific to African Americans.